The new vascular disrupting agent combretastatin-A1-disodium-phosphate (OXi4503) enhances tumour response to mild hyperthermia and thermoradiosensitization

14115 Background: CYT997 is a novel tubulin-binding small molecule which inhibits microtubule assembly and also demonstrates potent vascular-disrupting activity in preclinical tumour models. Methods: CYT997 was administered by continuous infusion over 24 hours every 3 weeks to patients with advanced cancer. Dose escalation proceeded by a standard phase I design (3 patients per dose level) for the first 18 patients; subsequently, an accelerated titration design (1 patient per dose level) was utilized. Intrapatient dose escalation was permitted. Pharmacokinetic (PK) analyses were performed in the first cycle. Tumour response was determined every second cycle using RECIST criteria. Pharmacodynamic effects on the tumour vasculature were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 22 patients (M/F: 11/11; median age 57.5, range 28–75) were enrolled with tumour types including melanoma (4), renal cell (4), colorectal (2), non-small cell lung (2) and adenoid cystic (2) carcinomas, mesothelioma (2) and others (6). A total of 66 cycles of CYT997 were administered (median 2/patient, range 1–6) over 10 dose levels (7, 14, 23, 35, 49, 65, 86, 114, 152 and 202 mg/m2). No dose-limiting toxicity was observed. Because of grade-2 injection site reactions in 2 patients (one each at dose levels 3 and 4), all subsequent patients received CYT997 via a central venous access device. Other toxicities included grade-2 renal toxicity at dose- level 8 in one patient with abnormal baseline renal function and grade-1 QTc prolongation in one patient at dose-level 10. No myelosuppression, gastrointestinal toxicity or clinically-significant cardiac toxicity were observed. PK data revealed dose-related increases in Cmax and AUC values. Six patients had stable disease after 4 cycles of CYT997. Conclusions: CYT997 was well tolerated at the doses studied and accrual to the 269 mg/m2 dose level will now proceed. No significant financial relationships to disclose.

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The Novel Vascular Disrupting Agent ANG501 Induces Cell Cycle Arrest and Enhances Endothelial Cell Sensitivity to Radiation

Cancer Growth and Metastasis ◽

10.4137/cgm.s2596 ◽

2009 ◽

Vol 2 ◽

pp. CGM.S2596 ◽

Cited By ~ 2

Author(s):

Shona T. Dougherty ◽

Sean E. Walker ◽

Peter D. Davis ◽

Graeme J. Dougherty

Keyword(s):

Cell Cycle ◽

Endothelial Cells ◽

Normal Cell ◽

Cell Cycle Progression ◽

Stress Proteins ◽

Vascular Disrupting Agent ◽

Heat Shock Stress ◽

Cell Cycling ◽

Vascular Disrupting

The efficacy of approaches in which vascular disrupting agents (VDA) are used in combination with conventional chemotherapy and/or radiation therapy in the treatment of cancer might be improved if there were a better understanding of the cellular and molecular changes induced in normal and malignant cells as a result of VD A exposure. Toward this goal, murine endothelial cells were treated in vitro with ANG501, a novel stilbene VDA developed in our laboratory, and alterations in gene expression determined by genome-wide microarray analysis and subsequently confirmed by Western blot analysis. Among the genes that were shown to be induced upon brief exposure to non-cytotoxic doses of ANG501 were several involved in the control of cell cycle progression and apoptosis, including p21Wafl and the heat shock/stress proteins hsp25, hsp70 and anti-B-crystallin. Reflecting such induction, functional studies confirmed that normal cell cycling is temporarily inhibited following treatment with ANG501 such that the majority of cells accumulate at the radiation-sensitive G2/M phase of the cell cycle at 6 hr. The effects were transient and by 24 hr normal cell cycling had largely resumed. Combination experiments confirmed that endothelial cells treated 6 hr previously with ANG501 were more readily killed by radiation. Importantly, significant effects were evident at clinically relevant radiation doses. Taken together these findings emphasize the need to consider the radiosensitizing activity of VD As when developing therapies in which these promising compounds are used in combination with radiation.

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